Chromosome segregation is a complex process that requires multiple levels of regulation. Our goal is to understand the regulation of various mitotic processes and to uncover the molecular function of proteins that have been identified as mitotic regulators but whose exact role is unknown. In the past year, we studied the protein Apq12, a novel protein involved in cell cycle regulation. Cells have regulatory mechanisms, called checkpoints, that monitor the presence of intracellular damage or structural errors, and arrest cell cycle progression until the damage or error is repaired. Consequently, mutations in various cell cycle genes do not lead to a detectable phenotype because checkpoint pathways compensate for defects that would otherwise be deleterious. To uncover novel cell cycle genes, we previously conducted a screen for mutations that lead to cell death when checkpoint pathways were inactive (Sarin et al, Genetics 2004). Through this screen we isolated APQ12, a gene that codes for an ER-associated protein of unknown function. The involvement of an ER protein in cell cycle regulation is intriguing, as this is one of the first examples that links ER function with cell cycle progression. Interestingly, the absence of Apq12 leads to intracellular damage that activated the spindle assembly checkpoint pathway, suggesting that Apq12 is involved in spindle or kinetochore function. We have been able to discern the orientation of Apq12 within the ER membrane and we are in the process of isolating Apq12- interacting proteins. Furthermore, we have identified several genes whose over-expression suppresses the lethality associated with the absence of both Apq12 and a functional spindle assembly checkpoint pathway. We are currently focusing our efforts on understanding the mechanism by which these genes promote viability and on the molecular function of Apq12. Note: due to changes in research priorities this project is temporarily suspended.